Psychiatric and neurological disorders are known to afflict millions of people worldwide resulting in substantial undue suffering. One serious and often destructive psychiatric disorder is depression. This disease is one of the most common and destructive illnesses prevalent in the United States and is estimated to afflict 35-40 million Americans at some point during their lives. Other important psychiatric and neurological disorders are anxiety disorders, mood disorders, personality disorders, psychosexual disorders, schizophrenia, drug abuse and dependence, and eating disorders. These disorders are known to affect people of all ages and the disorder may persist for a duration of a few weeks up to several decades.
Advances in neuroscience and molecular biology have lead to a better understanding of the roles of various biochemicals that cause psychiatric and neurological disorders. Research efforts have revealed that dopamine, norepinephrine, and serotonin play a role in many of these disorders. These biochemicals are important neurotransmitters that are implicated in a wide array of critical physiological processes.
Dopamine affects brain processes that control movement, emotional response, and ability to experience pleasure and pain. Regulation of dopamine plays a crucial role in our mental and physical health. It is thought that the dopamine transporter (DAT) is a primary mechanism for terminating the effects of synaptic dopamine and maintaining homeostatic levels of extracellular dopamine in the brain. Giros et al. Nature 1996, 379, 696. The dopamine transporter has been an important target for several drugs including methylphenidate, pemoline, and bupropion.
Norepinephrine (NE), also called noradrenaline, is a neurotransmitter that doubles part-time as a hormone. As a neurotransmitter, norepinephrine helps to regulate arousal dreaming, and moods. As a hormone, it acts to increase blood pressure, constrict blood vessels and increase heart rate, all of which are responses to stress.
Serotonin (5-hydroxytryptamine, 5-HT) is widely distributed in animals and plants. In the human body, serotonin is found mainly in the intestinal wall (where it causes increased gastrointestinal motility), blood vessels (where large vessels are constricted), and the central nervous system (CNS). Serotonin may be obtained from a variety of dietary sources; however, endogenous serotonin is synthesized in situ from tryptophan through the actions of the enzymes tryptophan hydroxylase and aromatic L-amino acid decarboxylase. The functions of serotonin are numerous and include control of appetite, sleep, memory and learning, temperature regulation, mood, behavior (including sexual and hallucinogenic behavior), cardiovascular function, muscle contraction, endocrine regulation, and depression.
The ability to treat psychiatric and neurological disorders has increased significantly over the last several decades. It has been found that compounds that selectively modulate the activity of dopamine, norepinephrine, or serotonin are effective treatments. For example, most forms of depression are associated with a deficiency of norepinephrine and/or serotonin at functionally important adrenergic or serotonergic receptors. Thus, treatment approaches have involved the use of agents (stimulants) that mimic norepinephrine, pharmaceuticals (MAOIs) that increase the levels of NE and 5-HT by inhibiting their metabolism, and drugs that increase these levels at the receptor by inhibiting the uptake of NE and 5-HT.
One class of antidepressants are tricyclic antidepressants (TCAs) which function by blocking the uptake of norepinephrine and, to varying degrees, the uptake of 5-HT. Within the class of TCA's, tertiary amines such as imipramine and amitriptyline are more selective inhibitors of 5-HT than catecholamines, compared with secondary amines such as desipramine. Trazodone and fluoxetine, both of which are marketed in the United States, serve to regulate the level of serotonine. Trazodone mediates the actions of 5-HT while fluoxetin is a selective inhibitor of 5-HT reuptake.
Narcolepsy is a disease that is thought to be caused by abnormalities in brain chemistry. Narcolepsy is a potentially disabling, lifelong condition estimated to afflict about one in every 1,000 people in the United States. The two primary symptoms of narcolepsy are excessive daytime sleepiness and cataplexy. People with narcolepsy are unable to resist falling asleep and do so regardless of the number of hours slept the previous night. Frequently, people with narcolepsy fall asleep at inappropriate times, for example while eating or in the middle of a conversation. Currently, there is no known cure for narcolepsy; however, the severity of the symptoms can be minimized with varying degrees of success with medications and adjustments of lifestyle.
The effects of excessive daytime sleepiness can be reduced by administration of provigil. Provigil is a wake-promoting agent allowing people with narcolepsy to participate in daily activities. However, provigil has been linked to side effects in some patients. These side effects include nausea, infection, nervousness, anxiety and/or insomnia.
Despite recent advances in the treatment of psychiatric and neurological disorders, many patients do not have satisfactory treatment options because they do not respond to a drug or the drug has intolerable side effects. For example, it is estimated that up to 30% of clinically diagnosed cases of depression are resistant to all known forms of drug therapy. In addition, many of the antidepressant drugs are linked to anticholinergic actions, cardiotoxicity, sedation, and/or weight gain. Hence, the need exists for new drugs to treat these patients, in addition to drugs with fewer side effects.